This invention relates to novel tetrahydroisoquinoline derivatives, to processes for their production and use, and to intermediates useful in the production thereof.
In U.S. patent applications Ser. No. 533,467, filed Dec. 16, 1974 now U.S. Pat. No. 4,001,411 and Ser. No. 607,810, filed Aug. 26, 1975, now U.S. Pat. No. 4,051,243 and in German Patent Applications P 23 62 539.0 and P 24 41 261.1, there are described processes for the preparation of 2-acyl-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinolines starting from 1-acylaminomethyl-2-halo-acetyl-1,2,3,4-tetrahydro-isoquinolines. The last-mentioned compounds are obtainable from the known 1-cyano-2-acyl-1,2-dihydro- or -1,2,3,4-tetrahydro-isoquinolines by hydrogenation in the presence of Raney nickel and subsequent reaction with a haloacetyl halide.
Some of the compounds of Formula I hereinafter which are excluded from Formula Ia are known from the U.S. Patent Applications mentioned above.
It has been found that even the starting materials for this reaction sequence, viz., the 1-cyano-2-acyl-1,2-dihydro- or -1,2,3,4-tetrahydroisoquinolines are frequently obtainable in yields which are technically not satisfactory. For example, 1-cyano-2-cyclohexylcarbonyl-1,2-dihydroisoquinoline is formed only in small amounts from isoquinoline, cyclohexanecarboxylic acid chloride and cyanides.
The hydrogenation of the 1-cyano-2-acyl-1,2-dihydro- or -1,2,3,4-tetrahydroisoquinolines in the presence of Raney nickel also does not proceed satisfactorily. Thus, from the reaction mixture which results in the case of the hydrogenation of 1-cyano-2-benzoyl-1,2-dihydroisoquinoline, a maximum of only 50% of 1-benzamidomethyl-TIS can be isolated.
It is an object of this invention to provide a novel, advantageous process for the preparation of 1-acylaminomethyl-1,2,3,4-tetrahydroisoquinolines as defined hereinafter.
A further object of this invention is to provide novel tetrahydroisoquinolines useful as pharmaceuticals in human and veterinary medicine.
Other objects will be apparent to those skilled in the art.
A further object of this invention is the provision of a novel synthesis for the preparation of 2-acyl-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino-[2,1-a]isoquinoline derivatives which are outstandingly effective anti-helmintically.
For the sake of brevity, hereinafter the designation "-TIS" is employed to mean "-1,2,3,4-tetrahydroisoquinoline." Consequently, e.g., the compound "1-cyclohexylcarboxamidomethyl-1,2,3,4-tetrahydroisoquinoline" can be designated as "1-cyclohexylcarboxamidomethyl-TIS."